Fig 2: Opposite expression of GLP-1R in glandular stomach of PO and SPD rats after diabetes induction. (a) RT (q)PCR analysis demonstrates that GLP-1R mRNA levels were significantly increased (P = 0.02) or decreased (P = 0.01) in diabetic PO and SPD rats (black columns), respectively, as compared to normoglycemic untreated animals (white columns). (b, c, d) Semiquantitative immunohistomorphological analysis of glandular GLP-1R expression of diabetic and control PO rats. (b) Significantly increased stain intensity of GLP-1R immunoreactive cells in neck area of principal glands of diabetic (black columns) compared with control (white columns) PO rats. The arbitrary lines presented in illustrations (c) and (d) and (f) and (g) divide the entire gastric glands into three areas named neck, mid, and bottom areas. The neck area includes very narrow isthmus and neck areas of gastric glands; mid area, the upper area of gastric gland base; bottom area, the deep area of gastric gland base. (c, d) GLP-1R immunostained longitudinal sections of glandular stomach mucosa (magnification ×10) demonstrate general increase of stain intensity of GLP-1R immunoreactive glandular cells (brown color) most prominently in the neck of principal glands of diabetic (d) compared with control (c) PO rats. (e, f, g) Semiquantitative immunohistomorphological analysis of glandular GLP-1R expression in diabetic and control SPD rats. (e) Significantly decreased stain intensity of GLP-1R immunoreactive cells in neck (P = 0.02) and mid areas (P = 0.04) of principal glands of diabetic (black columns) compared with control (white columns) SPD rats. (f, g) GLP-1R immunostained longitudinal sections of glandular stomach mucosa (magnification ×10) demonstrate a general decrease stain intensity (most prominent in the neck area) of GLP-1R immunoreactive glandular cells (brown color) in diabetic (g) compared with control (f) SPD rats. Data are presented as mean ± SD. Bar = 100 μm.

Fig 3: GLP-1R cellular association in gastric principal glands of PO and SPD rats. Longitudinal sections of gastric principal glands of PO (a, b, c) and SD rats (d, e, f). H&E staining (left panels) and GLP-1R immunostaining (right panels) are shown (magnification ×40). (a, d) Neck area of principal glands of PO (a) and SPD (d) rats is dominated by acid secreting parietal cells (solid arrows) which display strong GLP-1R immunoreactivity. Mucous secreting neck cells (broken arrows) demonstrate no GLP-1R immunoreactivity. (b, e) Mid area of principal glands of PO (b) and SPD (e) rats is populated by acid secreting GLP-1R immunostained parietal cells (solid arrows) and chief cells without GLP-1R immunoreactivity (square head arrows). (c, f) Bottom area of principal glands of PO (c) and SPD (f) rats. GLP-1R immunopositive enteroendocrine-like cells (head only arrows), parietal cells (solid arrows), and chief cells (square head arrows) without GLP-1R immunoreactivity are shown. Bar = 20 μm.

Fig 4: A schematic model displaying the opposite alterations of GLP-1/GLP-1R system in enteropancreatic axis in T1DM and T2DM experimental diabetes. (a) In STZ-induced T1DM, GLP-1 secretion from intestinal L cells and pancreatic alpha cells is increased (upward thin arrows). However, STZ toxicity causes severe loss of pancreatic beta cells and mild loss of extrapancreatic gastric glands parietal cells with the resulting decrease of the GLP-1 receptor (downward thin arrows). The discrepancy between increased GLP-1 secretion and reduced GLP-1R expression results in severely impaired GLP-1/GLP-1R signaling in pancreas and to a lesser degree in the stomach (broken thin and thick arrows). (b) HE diet-induced T2DM is characterized by increased GLP-1R on beta cells in pancreas and gastric parietal cells which are also increased in number as well as increased GLP-1 secretion from pancreatic alpha cells and extrapancreatic intestinal L cells (upward thin arrows). The joint increase in GLP-1 secretion and GLP-1R expression in enteropancreatic axis results in upregulation of endocrine and paracrine GLP-1/GLP-1R signaling in pancreas and stomach (thick arrows). P: pancreas; S: stomach; I: ileum.